Acambis hopes to build a flu vaccine that lasts

Aug 25, 2005 (CIDRAP News) – The British biotechnology firm Acambis recently announced its launching of a quest for the Holy Grail of influenza prevention: a vaccine that would protect people from the virus for many years and perhaps even stave off future pandemic strains.

With current technology, flu vaccines have to be retooled every year in a time-consuming effort to cope with minor mutations that enable the flu virus to avoid quick detection by the immune system. But a vaccine based on parts of the virus that stay the same, instead of those that often change, could eliminate the need to bring out a new model every year.

Acambis announced early this month that it was collaborating with Belgium's Flanders Interuniversity Institute for Biotechnology (known as VIB) to replace the annual flu vaccine with a perennial one.

"The aim of the research collaboration would be to generate a 'universal' vaccine candidate that would protect against both A and B strains of influenza and, more importantly, would not require annual changes to the formulation," the company said in its Aug 4 announcement.

The company hopes that such a vaccine could also protect people from a pandemic flu virus, which can arise from a major change, or "antigenic shift," in viral components. With disease experts warning that the H5N1 avian flu virus could turn into a pandemic strain any day, that prospect is doubly attractive. However, availability of such a vaccine is, at best, years away—too far in the future to help combat any near-term pandemic.

The frequent minor changes in flu viruses involve two of the virus's surface proteins, hemagglutinin and neuraminidase, represented by the H and N in names like "H5N1." Hemagglutinin and neuraminidase enable flu viruses to enter host cells and then exit them after replicating. Current vaccines target these highly mutable proteins, making it necessary to adjust the vaccines each year to match the circulating strains.

Acambis's vaccine effort focuses on a far less shifty viral protein, called M2. "A major component of the new [vaccine] candidates," the company said, "will be M2e, the extracellular domain of the ion channel protein M2, which is specific to influenza A. Being highly conserved, M2e is intended to elicit protective immune responses against all strains of influenza A. M2e is incorporated in a unique carrier system that forms highly immunogenic virus-like particles."

Ashley Birkett, Acambis's director of viral immunology in Cambridge, Mass., said the company is working on a separate technology for type B influenza. If the type A and B vaccines both prove effective, combining the two into one shot "would give us a truly universal vaccine," he told CIDRAP News.

The A type vaccine would potentially protect people against pandemic flu, since previous known pandemic strains were type A and future ones are expected to follow suit, Birkett said.

"The advantage of this approach is that the manufacturing relative to the vaccine would be much easier," he said. "It would be the same vaccine year after year."

Since the vaccine wouldn't have to be changed each year, manufacturing could be continuous, instead of occurring each spring and summer after health officials pick the flu strains they think will prevail the following winter. With year-round manufacturing, people could be immunized any time of year, not just in the fall or winter, and vaccine could be stockpiled, Birkett said.

Conventional production of flu vaccine involves growing whole copies of a weakened virus in chicken eggs (though several companies are working on growing flu viruses in cell culture). Acambis's experimental vaccine is manufactured with a "recombinant bacterial fermentation technology," in which bacteria are used to make selected viral proteins, rather than whole virus. "The bacteria can make single proteins for us," Birkett said.

With this technique, the production time for a batch of vaccine is "a matter of weeks," as compared with about 6 months for egg-based vaccine, he said. "But the main difference is you're going to be making the virus year-round. It really comes down to the fact that we don't have to change the product," he added.

Acambis said its initial vaccine candidate is "in pre-clinical development" and has been tested successfully in animals. Two recent journal articles describe successful tests of various versions of the vaccine in mice.

The reports, published in Virus Research and Virology, say that M2e generates only a weak immune response during flu infection and when used in a conventional vaccine. But when it is linked to an appropriate carrier, such as hepatitis B virus core (HBc) particles, it induces a strong antibody response. When various versions of the M2e-HBc combination were used with an adjuvant (a chemical that stimulates the immune system), they fully protected mice from a potentially lethal flu infection, the reports say.

Work on the vaccine has already been going on for several years. Acambis said it acquired the vaccine from Apovia, a US biotechnology firm, earlier this year. Apovia started developing the vaccine in 2000, after licensing the technology from VIB, where Walter Fiers led the research on which the vaccine is based.

Birkett said he couldn't predict when the firm might launch clinical trials or how long it might take to bring the vaccine to licensing, but indications are it will be a lengthy effort.

Theoretically, a perennial flu vaccine is a great concept, said Gregory Poland, MD, a vaccine expert at the Mayo Clinic in Rochester, Minn.

"One of the real problems we have is that each year, the vaccine is an educated guess," Poland told CIDRAP News, referring to the problem of predicting which flu strains will predominate in a given season. "The other problem is getting large numbers of people to get a vaccine every year."

A single vaccine that would reliably fend off the shifty virus for years would eliminate both of those difficulties. "A flu vaccine that could be given once, twice, or periodically would be a grand slam," said Poland, who is a professor of medicine in infectious diseases at the Mayo College of Medicine and directs the Mayo Vaccine Research Group and Program in Translational Immunovirology.

But Poland was cautious in assessing the likelihood of success.

"We need a proof of principle at this point," he said. "There are a number of entities trying to develop a similar vaccine. I do think it's theoretically possible. From an immunologic point of view, the key will be choosing the right antigen [viral protein] and knowing that the antigen is displayed early in the infection, so that an immune response can be generated early enough to abort the infection. My concern is if you find antigens that are displayed late in the infection, you may generate an immune response too late to do much good."

Birkett acknowledged that the experimental vaccine targets the virus later in its life cycle than conventional vaccines do. "But if you want a universal vaccine, you have to target a component that develops later in the life cycle," he said.

"It's a totally new vaccine approach," he said. "We're confident, we're hopeful, but until we do the [clinical] studies, we won't know for sure [if the vaccine will work]. If it does work, it'll be the Holy Grail. It could meet the need for influenza [protection] year after year."

Acambis is not the only organization pursuing a universal flu vaccine. The National Institute of Allergy and Infectious Diseases (NIAID) is supporting efforts by several other researchers on the same problem.

Andrew Pekosz of Washington University in St. Louis and David Milich of the Vaccine Research Institute in San Diego are working on a vaccine that, like Acambis's, targets the M2 protein of the influenza A virus, according to an article on the NIAID's influenza Web site.

Because relatively few copies of the M2 protein are present on the outer coat of the virus, an M2-based vaccine made from a normal flu strain generates only a weak immune response, the article notes. Milich is addressing this problem by developing a "bulked up" M2 vaccine that contains 240 copies of the protein, which stimulates the production of more antibodies.

Other researchers working on similar vaccines include Walter Gerhard at the Wistar Institute in Philadelphia and Gary Van Nest at the biotechnology company Dynavax, according to the NIAID. Gerhard's vaccine targets the M2 protein, while Van Nest is using another viral protein, called NP.

Poland predicts it will take years to bring a universal flu vaccine to market, if it can be done at all. "I wouldn't hold my breath that we're going to have a vaccine like this in the next couple of years," he said. "I think proof of principle you could get in a couple of years. For licensure of a vaccine like that, the typical cycle is going to be somewhere in the 7- to 10-year horizon." But he added that it might be possible to speed up the process, especially if the vaccine would be effective against a pandemic virus.